The invention relates to methods and compositions for the prevention, treatment, or management of gastrointestinal disorders or symptoms thereof, by administering one or more agent(s) or compound(s) that simultaneously or sequentially act on a 5-HT3 receptor, a 5-HT4 receptor, and either an H2 receptor or a proton pump.
Gastrointestinal disorders are common disorders that affect the gastrointestinal tract, i.e., the stomach and intestines. Various gastrointestinal disorders exist, including: gastro-esophageal reflux disease, emesis, gastrointestinal motility dysfunction, gastrointestinal ulcers, pathological hypersecretory conditions, and gastric hyperacidity. These diseases may be treated by various non-invasive means, such as administering to a patient a therapeutic agent, such as ZANTAC(copyright) (ranitidine), TRITEC(copyright) (ranitidine), AXID(copyright) (nizatidine), TAGAMET(copyright) (cimetidine), PREVACID(copyright) (lansoprazole), PEPCID(copyright), PEPCID AC(copyright) ACID CONTROLLER(trademark), MYLANTA AR ACID REDUCER(trademark) (famotidine), PRILOSEC(copyright) (omeprazole), and others. New pharmaceutical compounds and preparations are continually being developed.
U.S. Pat. Nos. 4,962,115, 5,057,525, and 5,137,896 (collectively xe2x80x9cVan Daelexe2x80x9d) disclose N-(3-hydroxy-4-piperidenyl)benzamides. These compounds are said to stimulate the motility of the gastrointestinal system. Van Deale states that the cis and trans diastereomeric racemates of these compounds may be obtained separately by conventional methods, and the cis and trans diastereomeric racemates may be further resolved into their optical isomers. One such racemate, Cisapride, is chemically named cis-4-amino-5-chloro-N-[1-[3-(4-fluorophenoxy)propyl]-3-methoxy-4-piperidinyl]-2-methoxybenzamide. Schapira et al., Acta Gastroenterolog. Belg., LIII:446-457 (1990). Gisapride is used primarily to treat gastroesophageal reflux disease (xe2x80x9cGERDxe2x80x9d), which is characterized as the backward flow of the stomach contents into the esophagus. Cisapride is commercially available as the racemic mixture of the cis(xe2x88x92) and cis(+) diastereomeric enantiomers of cisapride known as PROPULSID(copyright).
Benzamide derivatives have several prominent pharmacological actions due to their effects on neuronal systems modulated by the neurotransmitter serotonin. It has been reported that a major site of production and storage of serotonin is the enterochromaffin cell of the gastrointestinal mucosa. It was also reported that serotonin provides a powerful intestinal transit and decreasing absorption time, as occurs with diarrhea. This stimulating action is also associated with nausea and vomiting.
Because of their modulation of the serotonin neuronal system in the gastrointestinal tract, some benzamide derivatives are effective antiemetic agents and are used to control vomiting during cancer chemotherapy or radiotherapy. Costall et al., Neuropharmacology, 26:1321-1326 (1987). This action is the result of an ability to block serotonin at specific sites, particularly Type-3 5-hydroxytryptamine (5-HT3) receptors. Clarke et al., Trends in Pharmacological Sciences, 10:385-386 (1989). Chemotherapy and radiation therapy can induce nausea and vomiting by damaging enterochromaffin cells in the gastrointestinal tract. As a result, the neurotransmitter serotonin is released and stimulates both afferent vagal nerve fibers (thus initiating the vomiting reflex) and serotonin receptors in the chemoreceptor trigger zone of the area postrema region of the brain. The anatomical site for this action of the benzamide derivatives, and whether such action is central (CNS), peripheral, or a combination thereof, remains unresolved. Barnes et al., J. Pharm. Pharmacol., 40:586-588 (1988).
A second prominent action of certain benzamide derivatives is in augmenting gastrointestinal smooth muscle activity from the esophagus to the proximal small bowel, thus accelerating esophageal and small intestinal transit, as well as facilitating gastric emptying and increasing lower esophageal sphincter tone. Decktor et al., Eur. J. Pharmacol., 147:313-316 (1988). Although the benzamide derivatives are not cholinergic receptor agonists per se, the aforementioned smooth muscle effects may be blocked by muscarinic receptor blocking agents such as atropine or inhibitors of neuronal transmssions, such as the tetrodotoxin type that block sodium channels. Fernandez and Massingham, Life Sci., 36: 1-14 (1985). Similar blocking activity has been reported for the contractile effects of serotonin in the small intestine. Craig and Clarke, Brit. J. Pharmacol., 96: 247P (1989). It is believed that the primary smooth muscle effects of some benzamide derivatives are the result of an agonist action upon a class of serotonin receptors referred to as 5-HT4 receptors, which are located on interneurons in the myenteric plexus of the gut wall. Clarke et al., Trends in Pharmacological Sciences, 10: 385-386 (1989) and Dumuis et al., N. S. Arch. Pharmacol., 340: 403-410 (1989). Activation of these receptors subsequently enhances the release of acetylcholine from parasympathetic nerve terminals located near surrounding smooth muscle fibers. It is the combination of acetylcholine with its receptors on smooth muscle membranes which is the actual trigger for muscle contraction.
It has been reported that cisapride enters the central nervous system and binds to 5-HT4 receptors. This indicates that cisapride may have centrally-mediated effects. Cisapride is a potent ligand at 5-HT4 receptors, which are located in several areas of the central nervous system. Dumuis et al., N. S. Arch. Pharmacol, 340: 403-410 (1989). Modulation of serotonergic systems may have a variety of behavioral effects.
The co-administration of racemic cisapride with other therapeutic agents causes inhibitory problems with the metabolism of cisapride by the liver. For example, ketoconazole has a pronounced effect on cisapride kinetics resulting from the inhibition of the metabolic elimination of cisapride and leads to an 8-fold increase of the steady-state plasma levels. Physician""s Desk Reference(copyright), Medical Economics Co., Inc., p. 1308-1309, 52nd Edition (1998). Interaction of racemic cisapride and other therapeutic agents can also potentiate cardiovascular side effects, such as cardiotoxicity. This potentiation occurs when other drugs present in the patient""s system interfere with the metabolism of cisapride, thereby causing a build up of racemic cisapride in the body.
These interactions are a significant drawback to the use of racemic cisapride; in particular, because racemic cisapride is often used before, with, or immediately after another therapeutic agent. In addition, administration of racemic cisapride to a human has been found to cause adverse effects such as cardiac arrhythmia, including ventricular tachycardia, ventricular fibrillation, Qr prolongation, and torsades de pointes, central nervous system (xe2x80x9cCNSxe2x80x9d) effects, increased systolic pressure, interactions with other drugs, diarrhea, abdominal cramping, and cardiac depression.
Racemic cisapride in humans is metabolized mainly by oxidative N-dealkylation of the piperidine nitrogen or by aromatic hydroxylation occurring on either the 4-fluorophenoxy or benzamide rings. Meuldermans et al., Drug Metab. Dispos., 16(3):410-419 (1988); and Meuldermans et al., Drug Metab. Dispos., 16(3):403-409 (1988). Norcisapride, chemically named 4-amino-5-chloro-N-(3-methoxy-4-piperidinyl)-2-methoxybenzamide, is an active metabolite of cisapride.
Recently, investigators have reported that the optically pure (+) stereoisomer of the cisapride metabolite norcisapride exhibits many useful characteristics, but without certain side effects of racemic cisapride. Specifically, U.S. Pat. No. 5,739,151 discloses a method of eliciting an antiemetic effect and treating other conditions using optically pure (+) norcisapride.
Other agents or compounds which have been studied for the treatment of gastrointestinal diseases include proton pump inhibitors and H2 receptor antagonists. Proton pump inhibitors treat gastrointestinal diseases by inhibiting H+-K+ ATPase and thereby regulating acidity in gastric juices. H2 receptor antagonists inhibit histamine binding with H2 receptors to regulate gastric acid secretion. Goodman and Gilman, The Pharmacological Basis of Therapeutics, 9th Edition, pp. 901-915 (1996).
The concentration gradients of gastric acids across cell membranes vary widely. Perhaps the largest gradient in the body occurs across the plasma membrane of the parietal cells of the stomach lining, which secrete hydrochloric acid into gastric juice. Since the concentration of hydrochloric acid in gastric juice may be as high as 0.1 M and the concentration of H+ in the cells is about 10xe2x88x927 M, parietal cells can secrete H+ ions against a concentration gradient of about 1 million to 1. A membrane-bound enzyme called H+-K+ ATPase facilitates active transport of H+ across membranes against concentration gradients in exchange for K+ to form gastric hydrochloric acid. For each molecule of cytosolic ATP hydrolyzed to ADP and phosphate, 2 H+ ions are transported across the plasma membrane from the cytosol to the stomach. Goodman and Gilman, The Pharmacological Basis of Therapeutics, 9th Edition, pp. 901-915 (1996).
Proton pump inhibitors suppress gastric acid secretion, the final step of acid production, by specific inhibition of the H+-K+ ATPase enzyme system at the secretory surface of gastric parietal cells. Proton pump inhibitors include benzimidazole compounds, for example, omeprazole (PRILOSEC(copyright)), lansoprazole (PREVACID(copyright)), and pantoprazole. These proton pump inhibitors contain a sulfinyl group situated between substituted benzimidazole and pyridine rings. At neutral pH, omeprazole, lansoprazole, and pantoprazole are chemically stable, lipid soluble, weak bases that are devoid of inhibitory activity. These uncharged weak bases reach parietal cells from the blood and diffuse into the secretory canaliculi, where the drugs become protonated and thereby trapped. The protonated species rearranges to form a sulfenic acid and a sulfenamide, the latter species capable of interacting with sulfhydryl groups of H+-K+ ATPase. Full inhibition occurs with two molecules of inhibitor per molecule of enzyme. The specificity of the effects of proton pump inhibitors is believed to derive from: a) the selective distribution of H+-K+ ATPase; b) the requirement for acidic conditions to catalyze generation of the reactive inhibitor; and c) the trapping of the protonated drug and the cationic sulfenamide within the acidic canuliculi and adjacent to the target enzyme. Goodman and Gilman""s The Pharmacological Basis of Therapeutics, 9th Edition, pp. 901-915 (1996).
H2 receptor antagonists competitively inhibit the interaction of histamine with H2 receptors. They are highly selective and have little or no effect on H1 receptors. Although H2 receptors are present in numerous tissues, including vascular and bronchial smooth muscle, H2 receptor antagonists interfere remarkably little with physiological functions other than gastric acid secretion. H2 receptor antagonists include nizatidine (AXID(copyright)), ranitidine (ZANTAC(copyright) and TRITEC(copyright)), famotidine (PEPCID AC(copyright)), and cimetidine (TAGAMET(copyright)). Goodman and Gilman""s The Pharmacological Basis of Therapeutics, 9th Edition, pp. 901-915 (1996).
H2 receptor antagonists inhibit gastric acid secretion elicited by histamine, other H2 agonists, gastrin, and, to a lesser extent, muscarinic agonists. H2 receptor antagonists also inhibit basal and nocturnal acid secretion, and this effect contributes in a major way to their clinical efficacy.
Although therapeutic agents are available, there remains a need for a more effective, broad-spectrum treatment or therapy for gastrointestinal disorders. For example, it is desirable to have safe and effective methods and compositions for preventing, treating, and managing gastrointestinal disorders without adverse effects or adverse drug-drug interactions.
The invention encompasses the prevention, treatment, or management of gastrointestinal disorders by biological action at three different sites: action at 5-HT3 receptors, 5-HT4 receptors, and either H2 receptors or proton pumps. The use of triple action is considered to provide an unexpectedly superior therapeutic profile. The use of this triple action therapy can be less toxic and/or more potent for preventing, treating, and managing gastrointestinal disorders than the use of agents that act on any of the three sites alone.
In one embodiment, three therapeutic agents or compounds are used, one providing action at 5-HT3 receptors, another providing action at 5-HT4 receptors, and the third being either a proton pump inhibitor or an H2 receptor antagonist. For example, in a preferred embodiment, cisapride, ondansetron, and either a proton pump inhibitor or an H2 receptor antagonist are used to prevent, treat, or manage gastrointestinal disorders. In a more preferred embodiment, either optically pure (+) cisapride or optically pure (xe2x88x92) cisapride, or a pharmaceutically acceptable salt thereof, optically pure R(+) ondansetron, or a pharmaceutically acceptable salt thereof, and either a proton pump inhibitor or an H2 receptor antagonist are used.
In another embodiment, the invention encompasses the synergistic use of two or more agents or compounds to provide triple site action on 5-HT3 receptors, 5-HT4 receptors, and either H2 receptors or proton pumps. In a preferred embodiment, two agents or compounds are used, one providing dual action at 5-HT3 receptors and 5-HT4 receptors, and another providing action either at H2 receptors or proton pumps. For example, in this preferred embodiment, optically pure (+) norcisapride, or a pharmaceutically acceptable salt thereof, which has both 5-HT3 and 5-HT4 activity, and either a proton pump inhibitor or H2 receptor antagonist are used to prevent, treat, or manage gastrointestinal disorders.
This invention also encompasses the use of two separate pharmaceutical compositions adapted for the prevention, treatment, or management of a patient suffering from gastrointestinal disorders or symptoms thereof, one which comprises a therapeutically effective amount of optically pure (+) norcisapride, or a pharmaceutically acceptable salt thereof, and another which a therapeutically effective amount of either a proton pump inhibitor or H2 receptor antagonist.
Alternatively, the invention also encompasses pharmaceutical compositions comprising optically pure (+) norcisapride, or a pharmaceutically acceptable salt thereof, in combination with a either a proton pump inhibitor or an H2 receptor antagonist. Such single unit dosage forms comprise from about 0.5 mg to about 500 mg of optically pure (+) norcisapride, or a pharmaceutically acceptable salt thereof, and from about 1 mg to about 200 mg of a proton pump inhibitor or from about 1 mg to about 2400 mg an H2 receptor antagonist, in a suitable carrier.
The pharmaceutical compositions and methods of the invention, particularly those which comprise a therapeutically effective amount of optically pure (+) norcisapride, or a pharmaceutically acceptable salt thereof, can be used to prevent or alleviate symptoms of gastrointestinal disorders, while reducing or avoiding adverse effects associated with administration of conventional treatments such as conventional 5-HT3 receptor antagonists, 5-HT4 receptor agonists or antagonists, H2 receptor antagonists, and proton pump inhibitors. Moreover, the compositions and methods of the present invention encompass the treatment, prevention or management of gastrointestinal disorders while reducing or avoiding adverse drug-drug interactions which are known to occur with the use of existing commercial agents, such as racemic cisapride.